Sepsis is a disorder which occurs when a relative large amount of micro-organisms or fragments thereof enters the body. It is also referred to as endotoxemia or endotoxic shock. Endotoxin, or lipopolysaccharide (LPS) is a component of the outer cell membrane of Gram-negative bacteria. Lipoteichoic acid (LTA) is a component of the outer membrane of Gram-positive bacteria that can also give rise to sepsis. The intestines, especially the colon, are a reservoir of LPS and Gram-negative bacteria, such as the common inhabitant Escherichia coli, but also of LTA and Gram-negative bacteria. LPS as well as LTA can enter the systemic circulation by direct translocation from the gut or via translocation of Gram-negative and/or Gram-positive bacteria across the intestinal wall.
The presence of Gram-negative and/or positive bacteria and LPS and/or LTA in the gut is of no problem for a healthy person. However, in persons or animals with imparted barrier function of the gut, for instance caused by ischemia, surgery, chronic inflammation, radiotherapy, trauma, use of certain drugs, such as NSAID's or chemotherapeutics, critically ill persons such as persons under intensive supervision, or persons infected by invasive pathogens, LPS, LTA, Gram positive bacteria and/or Gram-negative bacteria can cross the intestinal wall and reach the circulation. Once these bacteria have entered the system, LPS and/or LTA are released, which release is mainly due to a high activity of the phagocytic system. This infection process can also occur via the lungs (or during infections) or via peripheral body parts (e.g. after traumata caused by accidents, or during decubitus, during the last phases of some pregnancy disorders (HELLP syndrome) or during transfusions).
The release of LPS and/or LTA in the body can lead to an acute phase response and sepsis if LPS and/or LTA are not properly neutralized. Such unproper neutralisation may occur in animals/persons with a compromised immune function, as is often the case after malnutrition, fasting, surgery, ischeamic conditions, severe burn injury, chronic infection, cancer therapy, imparted liver or spleen function, with critically ill persons, and also with persons that have to recover directly after severe surgery.
The acute phase response can be determined by measuring levels of C reactive protein in blood. C-reactive protein is an acute phase protein in man and an important component of the innate immune system. C-reactive protein activates the classical pathway of complement, which is one of its main mechanisms in providing host defense. It has recently been recognized that C-reactive protein interacts with the cells of the immune system by binding to Fc gamma receptors. It may thus bridge the gap between innate and adaptive immunity and provide an early, effective antibacterial response. Furthermore, as it protects against the damaging inflammatory response to lipopolysaccharide and cytokines, it may prevent the lethal side-effects of bacterial products. Risk of sepsis can be determined by measuring in vivo protein synthesis in cells of the immune system such as T lymphocytes as described in Januszkiewicz et al. Clin. Nutr. 2001, 20(2), 181-182.
Sepsis can lead to multiple organ failure or death. It is therefore of great importance to find a method to treat, and especially prevent sepsis. Several approach have been proposed in the prior art to alleviate the symptoms or prevent or treat sepsis.
One approach has been given in WO 98/32428 which describes the use of choline in an enteral feeding for the reduction and/or prevention of endotoxin induced injury and mortality. The amount administered is 1.5 to 20 g per day. Choline is administered as choline tartrate.
Another approach has made use of phospholipids such as given in U.S. Pat. No. 5,434,183 which describes phospholipids containing ω-3 fatty acids DHA and EPA in combination with vegetable oil and/or marine oil for anti-inflammatory and/or immunosuppressive effects in the treatment of rheumatoid arthritis and sepsis. This enables the obtention of a very low level of serum cholesterol and serum triglycerides.
WO 96/04916 describes protein and peptide free intravenous injection preparations containing at least one phospholipid in combination with cholanoic acid or cholanoic acid salt for the prophylaxis and therapy of endotoxin related conditions. Optionally a neutral lipid can be added.
JP 05320043 describes a lipopolysaccharide scavenger consisting of phospholipids, in particular phosphatidyl choline, cholesterol and saturated fatty acids, in particular myristic acid. These components are converted into liposomes which are used in a solution for intravenous administration for prevention or treatment of ischemia or tissue injuries after ischemia. A suitable concentration ratio of cholesterol to phosphatidyl choline to myristic acid is 5-10:5-10:1-5.
U.S. Pat. No. 4,474,773 also describes the administration of the combination of phospholipids, triglycerides, and cholesterol for treating, among others, dysfunctions of the immune system, the administration according to U.S. Pat. No. 4,474,773 being advantageously made intravenously.
The drawback of the compositions of the prior art for treating sepsis is that the formulations are complex, e.g. a liposome. A further drawback is that parenteral administration is intended which poses a greater risk to the patient. There is thus a need for a relatively simple, effective, safe preparation for the prevention and treatment of sepsis.
It has now been found that sepsis can be effectively prevented and/or treated by means of an enteral composition comprising phospholipids, triglycerides and cholesterol or precursors thereof.
The present invention is based on the finding that LPS and/or LTA are detoxified in the circulation by incorporation into lipoproteins such as LDL (Low Density Lipoprotein), VLDL (Very Low Density Lipoprotein), chylomicrons and HDL (High Density Lipoprotein), in particular chylomicrons. It is believed by the inventors that chylomicrons play an important role in absorbing and transporting lipophilic substances in general such as food components and toxins (e.g. LPS and/or LTA), which can enter the body via the intestine but which can also be formed in case of elimination of remnants of dead bacterial cells in parts of the body. Chylomicrons are released in the gut associated lymphoid tissue (GALT) and take up LPS and/or LTA that are released after lyses of bacteria in the enterocytes and in particular in the lymph nodes. The chylomicrons are transported from the lymph nodes via the ductus thoracicus to the angulus venosus sinister, which transports the chylomicrons, and other lipoproteins, to the heart, which then transports them to the Reticulo Endothelial System (in particular the spleen) and the liver (Kupffer cells). Chylomicrons can thus also be used as a vehicle for delivery in the liver of lipid soluble substances, thereby preventing losses which can occur from malabsorption.
Maintaining the natural level of chylomicrons, not only in blood plasma, but especially in GALT e.g. over a relatively large part of the length of the gut, ensures that most of the LPS and/or LTA which are released in several locations of the body e.g. in the lungs or gut, can be neutralized, substantially decreasing the risk of locally occurring high levels of LPS and/or LTA.
In view of these findings, it is thus essential according to the invention, contrary to the prior art, to administer the combination of phospholipids, triglycerides, and cholesterol as an enteral composition and not an intravenous composition. The combination of phospholipids, triglycerides and cholesterol is digested in the intestine ensuring a relatively constant release of chylomicrons for a prolonged period of time in GALT since the product is relatively slowly digested. Further, the combination of phospholipids, triglycerides and cholesterol of the invention has the advantage that the ingredients used need no specific pretreatments such as liposome formation which results in an effective product with a relatively low cost price. Further, enteral administration of the composition is simple and safe.
Compared to U.S. Pat. No. 4,474,773 which provides the intravenous administration of phospholipids, triglycerides and cholesterol, it has now been found, as above explained, that the enteral administration favors the formation of chylomicrons in GALT, thereby providing effective prevention and/or treatment of sepsis. In this respect, it is believed that the teaching of U.S. Pat. No. 4,474,773 would be detrimental to such prevention and/or treatment. Indeed, U.S. Pat. No. 4,474,773 provides the stimulation of the immune system by increasing the lymphocyte production. However, a problem encountered with this stimulation is that cytokines are in turn produced, which latter components are involved in the pro-inflammatory response that underlies sepsis (Intensive Care Med. 200;26 Suppl. 1:S124-8, Immunomodulatory therapy in sepsis, Kox W. J. et al.). This is further confirmed by Inflamm. Res. 1998 May; 47(5):201-10, “The inflammatory basis of trauma/shock associated multiple organ failure”, Yao Y. M. et al, which describes that activation of the immune system may produce a generalized inflammation finally leading to sustained inflammation and multiple organ damage. Accordingly, though following the teaching of U.S. Pat. No. 4,474,773, a stimulation of the immune system would be provided, this would nevertheless be detrimental to the treatment and/or prevention of sepsis.
Wang X. D. et al describe in Scand. J. Gastroenterol 1994:1117-1121 that the enteric administration of phospholipids significantly reduced the incidence of bacterial translocation after 90% hepatectomy in rats. They describe that bacterial translocation under certain conditions may cause sepsis or bacteremia. It is then concluded that the decrease in bacterial translocation is probably the result of phospholipids nourishing the intestinal mucosa and maintaining the intestinal barrier or by preventing of the barrier function as mucosal surfactant. However, this article makes no mention of chylomicrons, let alone of its relation with the prevention or treatment of sepsis.
Still another approach has been given by WO 01/19356 which prescribes the enteral administration of the combination of medium chain triglycerides and lipid to prevent sepsis.